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1.  CD24 genetic variants contribute to overall survival in patients with gastric cancer 
World Journal of Gastroenterology  2016;22(7):2373-2382.
AIM: To investigate the role of single nucleotide polymorphisms (SNPs) in CD24 gene in susceptibility and overall survival of gastric cancer (GC).
METHODS: We genotyped 3 tagging SNPs of CD24-P-534 in the promoter region, P170 in the coding region of exon 2 and P1527 in the 3′ untranslated region - using polymerase chain reaction-restriction fragment length polymorphism in specimens from 679 histologically-confirmed GC cases, 111 gastric atrophy (GA) cases and 976 tumor-free controls. Serum immunoglobulin G antibodies to Helicobacter pylori (H. pylori) of all subjects were detected by enzyme-linked immunosorbent assay. CD24 expression was evaluated by immunohistochemistry in 131 GC specimens. Correlations between SNPs and risk of GC or GA were shown by P values and odd ratios (ORs) with 95% confidence intervals (95%CI) compared with the most common genotype of each SNP using the unconditional logistic regression model after adjusting for age, sex and H. pylori infection. Survival within each SNP group was plotted by Kaplan-Meier method and compared by log-rank test (recessive model). Hazard ratios with 95%CIs were computed by Cox regression model after adjusting for age, sex, histological type, tumor differentiation, clinical stage and post-operational chemotherapy.
RESULTS: All of the three loci were in Hardy-Weinberg equilibrium in the control group. Median follow-up time for the 600 GC patients included in the survival analysis was 36.2 mo (range, 2.1-66.7 mo; 95%CI: 34.3-36.5 mo). Patients with the P-534 A/A genotype had significantly shorter survival (HR = 1.38, 95%CI: 1.01-1.88, P = 0.042) than did the C/C or C/A genotype carriers after adjusting for age, sex, histological type, tumor differentiation, clinical stage and post-operational chemotherapy. This trend was more evident in patients who lived longer than 2.5 years (HR = 7.55, 95%CI: 2.16-26.32, P = 0.001). The P170 T/T genotype was associated with a shorter lifespan than the non-T/T genotypes, but not significantly so. None of the three genetic variants was found to be associated with risk of GC (including tumor stage, grade and distant metastasis) or with risk of gastric atrophy. Furthermore, no difference of CD24 expression was found among the genotypes.
CONCLUSION: The P-534 site in CD24 gene affects the overall survival of gastric cancer and may serve as a prognostic marker for gastric cancer.
doi:10.3748/wjg.v22.i7.2373
PMCID: PMC4735012  PMID: 26900300
Gastric cancer; CD24; Single nucleotide polymorphisms; Gastric atrophy; Overall survival
2.  Low c-Met expression levels are prognostic for and predict the benefits of temozolomide chemotherapy in malignant gliomas 
Scientific Reports  2016;6:21141.
Aberrant c-Met has been implicated in the development of many cancers. The objective of this study was to identify an unfavorable prognostic marker that might guide decisions regarding clinical treatment strategies for high-grade gliomas. C-Met expression was measured using immunohistochemistry in 783 gliomas, and we further analyzed c-Met mRNA levels using the Agilent Whole Genome mRNA Microarray in 286 frozen samples. In vitro, we performed cell migration and invasion assays. Cell sensitivity to temozolomide (TMZ) chemotherapy was determined using MTT assays. Both mRNA and protein levels of c-Met were significantly associated with tumor grade progression and inversely correlated with overall and progression-free survival in high-grade gliomas (all P < 0.0001). These findings were nearly consistent at the mRNA level across 3 independent cohorts. Multivariable analysis indicated that c-Met was an independent prognostic marker after adjusting for age, preoperative Karnofsky Performance Status (KPS) score, the extent of resection, radiotherapy, TMZ chemotherapy, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Further analysis in vitro revealed that downregulating the expression of c-Met dramatically inhibited cell migration and invasion capacities, enhanced sensitivity to TMZ chemotherapy in H4 and U87 glioma cells. Our results suggest that c-Met may serve as a potential predictive maker for clinical decision making.
doi:10.1038/srep21141
PMCID: PMC4754763  PMID: 26879272
3.  Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction 
Abstract
It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll‐like receptors (TLRs) that respond to pathogen‐ and damage‐associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4‐mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (Bmax) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4‐blocking antibodies. We conclude that the expression, ligand‐binding capacity and pro‐inflammatory function of cardiomyocyte TLR4 are up‐regulated after long‐term MI, which promote inflammation and exacerbate heart failure.
doi:10.1111/jcmm.12659
PMCID: PMC4687701  PMID: 26290459
heart failure; inflammation; toll‐like receptor; cardiomyocyte
4.  Tumor-induced VEGF-C overexpression in retroperitoneal lymph nodes in VX2 carcinoma-bearing rabbits 
Objective
To establish the retroperitoneal lymph node (RLN) metastasis model of cervical carcinoma in rabbits and evaluate the relationship of vascular endothelial growth factor-C (VEGF-C) expression and the lymph node status.
Methods
Forty-eight rabbits were injected with VX2 cells or RPMI solution at muscular mucosae of the myometrium 0.5 cm away from the cervix. Animals were treated with or without cis-diamminedichloroplatinum(II) (cisplatin: DDP) and sacrificed on days 15, 21, and 27 post-VX2 or RPMI injections. Tumor mass and RLNs were examined histopathologically. Quantitative real-time PCR was used to examine the changes in VEGF-C mRNA expression. Levels of VEGF-C protein expression in tissues were determined using immunohistochemistry staining.
Results
Development of VX2 cervical carcinoma and the RLNs metastasis was confirmed with pathological examination. Significantly increased tumor volume was observed on days 15, 21, and 27 postinjection (P<0.05). The enlargement of RLNs was found on day 21. Expression of VEGF-C was significantly upregulated in peripheral white blood cells, tumor mass, and RLNs in an association with cancer progression. DDP resulted in a suppression of VEGF-C expression, whereas the influences on tumor mass and lymphatic metastasis were insignificant.
Conclusion
Elevated VEGF-C expressions in peripheral white blood cells and RLNs are associated with tumor progression and lymphatic metastasis. DDP treatment inhibits VEGF-C expression and fails to protect against metastatic cervical cancer.
doi:10.2147/DDDT.S89810
PMCID: PMC4639523  PMID: 26604693
VEGF-C; retroperitoneal lymph nodes; VX2; cisplatin; lymphatic metastasis; peripheral blood
5.  Nitric Oxide Isotopic Analyzer Based on a Compact Dual-Modulation Faraday Rotation Spectrometer 
Sensors (Basel, Switzerland)  2015;15(10):25992-26008.
We have developed a transportable spectroscopic nitrogen isotopic analyzer. The spectrometer is based on dual-modulation Faraday rotation spectroscopy of nitric oxide isotopologues with near shot-noise limited performance and baseline-free operation. Noise analysis indicates minor isotope (15NO) detection sensitivity of 0.36 ppbv·Hz−1/2, corresponding to noise-equivalent Faraday rotation angle (NEA) of 1.31 × 10−8 rad·Hz−1/2 and noise-equivalent absorbance (αL)min of 6.27 × 10−8 Hz−1/2. White-noise limited performance at 2.8× the shot-noise limit is observed up to ~1000 s, allowing reliable calibration and sample measurement within the drift-free interval of the spectrometer. Integration with wet-chemistry based on acidic vanadium(III) enables conversion of aqueous nitrate/nitrite samples to gaseous NO for total nitrogen isotope analysis. Isotopic ratiometry is accomplished via time-multiplexed measurements of two NO isotope transitions. For 5 μmol potassium nitrate samples, the instrument consistently yields ratiometric precision below 0.3‰, thus demonstrating potential as an in situ diagnostic tool for environmental nitrogen cycle studies.
doi:10.3390/s151025992
PMCID: PMC4634453  PMID: 26473876
Faraday effect; optical sensing and sensors; spectroscopy; nitrogen cycle; nitric oxide; isotopic ratiometry
6.  The Role of Dopaminergic VTA Neurons in General Anesthesia 
PLoS ONE  2015;10(9):e0138187.
Recent studies have demonstrated that the central dopaminergic system is implicated in the mechanism underlying general anesthesia. Here, we investigated whether dopaminergic ventral tegmental area (VTA) neurons participate in general anesthesia. Dopaminergic VTA neurons were selectively ablated from male Sprague Dawley rats via the bilateral infusion of 6-hydroxydopamine (6-OHDA) into the VTA. Two weeks after infusion, the number of dopaminergic neurons in the bilateral VTA was markedly reduced in the 6-OHDA-treated rats compared with the vehicle-treated rats. These bilateral VTA lesions significantly prolonged the recovery time for propofol but did not significantly alter its onset time or 50% effective dose (ED50) value. In addition, the anesthetic responses to isoflurane and ketamine were unaffected by the VTA lesions. Our findings suggested that dopaminergic VTA neurons might be involved in the emergence from propofol anesthesia.
doi:10.1371/journal.pone.0138187
PMCID: PMC4580504  PMID: 26398236
7.  TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas 
Oncotarget  2015;6(28):24871-24883.
IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup.
PMCID: PMC4694799  PMID: 26314843
TERT promoter; IDH; gliomas; radiation therapy; chemotherapy
8.  Phylogenetic Relationships and Evolution of the Androecia in Ruteae (Rutaceae) 
PLoS ONE  2015;10(9):e0137190.
Ruta, which belongs to tribe Ruteae, is the type genus of the subfamily Rutoideae and the family Rutaceae. Molecular systematic studies have shown that the genera in Ruteae are closer related to Aurantioideae than to most other genera of Rutoideae, some of the genera traditionally placed in Ruteae have been shown to be nested within the Aurantioideae clade, but the diagnostic characters for determining new patterns in the relationship are poor. In this study, we investigated the floral development of Boenninghausenia in Ruteae (sensu stricto), Haplophyllum in the basal position of Aurantioideae and Murraya in traditional Aurantioideae using scanning electron microscopy. The androecium of Boenninghausenia is obdiplostemony. As androecia in other genera within Ruteae (s.s.) are also obdiplostemonous, reconstruction of the ancestral state indicates that obdiplostemony is an ancestral character in this clade. Because the androecia of Haplophyllum and Murraya are also obdiplostemonous, obdiplostemony is also an ancestral character in Aurantioideae clade. The ancestral state reconstruction indicates this character can serve as a synapomorphy of the Ruteae-Aurantioideae clade. The results of our work also shed light on the evolution of the androecium in Rutaceae, as the obdiplostemony of this group is clearly derived from haplostemony in the ancestral genera in Rutaceae and has develop into polyandry by increasing antepetalous stamens.
doi:10.1371/journal.pone.0137190
PMCID: PMC4557828  PMID: 26332986
9.  Pituitary carcinoma with intraspinal metastasis: report of two cases and review of the literature 
Pituitary carcinomas are rare malignant neoplasms with diagnostic and management challenges. Patients with pituitary carcinomas have extremely poor outcomes. In this report, the authors describe two cases of pituitary carcinomas with intraspinal metastasis (Case 1: 42-year-old man with a history of pituitary adenoma 16 years ago developed an intraspinal lesion at C4-C5; Case 2: 26-year-old women with a history of growth hormone-producing pituitary adenoma 9 years ago developed intraspinal lesion in the sacral canal). Both patients underwent spine surgery. The intraspinal lesions were confirmed as metastatic pituitary carcinomas based on the histomorphology and immunohistochemical stains. The authors reviewed the literature for the diagnosis, treatment, and prognosis of intraspinal metastasis from pituitary carcinomas.
PMCID: PMC4583975  PMID: 26464743
Pituitary carcinoma; intraspinal metastasis; pituitary adenoma; management
10.  De Novo Assembly of the Donkey White Blood Cell Transcriptome and a Comparative Analysis of Phenotype-Associated Genes between Donkeys and Horses 
PLoS ONE  2015;10(7):e0133258.
Prior to the mechanization of agriculture and labor-intensive tasks, humans used donkeys (Equus africanus asinus) for farm work and packing. However, as mechanization increased, donkeys have been increasingly raised for meat, milk, and fur in China. To maintain the development of the donkey industry, breeding programs should focus on traits related to these new uses. Compared to conventional marker-assisted breeding plans, genome- and transcriptome-based selection methods are more efficient and effective. To analyze the coding genes of the donkey genome, we assembled the transcriptome of donkey white blood cells de novo. Using transcriptomic deep-sequencing data, we identified 264,714 distinct donkey unigenes and predicted 38,949 protein fragments. We annotated the donkey unigenes by BLAST searches against the non-redundant (NR) protein database. We also compared the donkey protein sequences with those of the horse (E. caballus) and wild horse (E. przewalskii), and linked the donkey protein fragments with mammalian phenotypes. As the outer ear size of donkeys and horses are obviously different, we compared the outer ear size-associated proteins in donkeys and horses. We identified three ear size-associated proteins, HIC1, PRKRA, and KMT2A, with sequence differences among the donkey, horse, and wild horse loci. Since the donkey genome sequence has not been released, the de novo assembled donkey transcriptome is helpful for preliminary investigations of donkey cultivars and for genetic improvement.
doi:10.1371/journal.pone.0133258
PMCID: PMC4514889  PMID: 26208029
11.  Effects of Curculigoside on Memory Impairment and Bone Loss via Anti-Oxidative Character in APP/PS1 Mutated Transgenic Mice 
PLoS ONE  2015;10(7):e0133289.
Alzheimer's disease (AD) and osteoporosis are two closely related multifactorial progressively degenerative diseases that predominantly affect aged people. These two diseases share many common risk factors, including old age, being female, smoking, excessive drinking, low estrogen, and vitamin D3 levels. Additionally, oxidative damage and the dysfunction of the antioxidant system play important roles in the pathogenesis of osteoporosis and AD. Aβ not only leads to impaired memory but also plays a crucial role in the demineralization process of bone tissues of older people and women with menopause. Curculigoside can promote calcium deposition and increase the levels of ALP and Runx2 in osteoblasts under oxidative stress via anti-oxidative character. Therefore, we investigated the effects of CUR on the spatial learning and memory by the Morris water maze and brain immunohistochemistry, and bone microstructure and material properties of femurs by micro-computed tomography and mechanical testing in APP/PS1 mutated transgenic mice. Oral administration of CUR can significantly enhance learning performance and ameliorate bone loss in APP/PS1 mutated transgenic mice, and the mechanism may be related to its antioxidant effect. Based on these results, CUR has real potential as a new natural resource for developing medicines or dietary supplements for the prevention and treatment of the two closely linked multifactorial progressive degenerative disorders, AD and osteoporosis.
doi:10.1371/journal.pone.0133289
PMCID: PMC4505858  PMID: 26186010
12.  Origin and evolution of Petrocosmea (Gesneriaceae) inferred from both DNA sequence and novel findings in morphology with a test of morphology-based hypotheses 
BMC Plant Biology  2015;15:167.
Background
Petrocosmea Oliver (Gesneriaceae) currently comprises 38 species with four non-nominate varieties, nearly all of which have been described solely from herbarium specimens. However, the dried specimens have obscured the full range of extremely diverse morphological variation that exists in the genus and has resulted in a poor subgeneric classification system that does not reflect the evolutionary history of this group. It is important to develop innovative methods to find new morphological traits and reexamine and reevaluate the traditionally used morphological data based on new hypothesis. In addition, Petrocosmea is a mid-sized genus but exhibits extreme diverse floral variants. This makes the genus of particular interest in addressing the question whether there are any key factors that is specifically associated with their evolution and diversification.
Results
Here we present the first phylogenetic analyses of the genus based on dense taxonomic sampling and multiple genes combined with a comprehensive morphological investigation. Maximum-parsimony, maximum likelihood and Bayesian analyses of molecular data from two nuclear DNA and six cpDNA regions support the monophyly of Petrocosmea and recover five major clades within the genus, which is strongly corroborated by the reconstruction of ancestral states for twelve new morphological characters directly observed from living material. Ancestral area reconstruction shows that its most common ancestor was likely located east and southeast of the Himalaya-Tibetan plateau. The origin of Petrocosmea from a potentially Raphiocarpus-like ancestor might have involved a series of morphological modifications from caulescent to acaulescent habit as well as from a tetrandrous flower with a long corolla-tube to a diandrous flower with a short corolla-tube, also evident in the vestigial caulescent habit and transitional floral form in clade A that is sister to the remainder of the genus. Among the five clades in Petrocosmea, the patterns of floral morphological differentiation are consistent with discontinuous lineage-associated morphotypes as a repeated adaptive response to alternative environments.
Conclusion
Our results suggest that the lineage-specific morphological differentiations reflected in the upper lip, a functional organ for insect pollination, are likely adaptive responses to pollinator shifts. We further recognize that the floral morphological diversification in Petrocosmea involves several evolutionary phenomena, i.e. evolutionary successive specialization, reversals, parallel evolution, and convergent evolution, which are probably associated with adaptation to pollination against the background of heterogeneous abiotic and biotic environments in the eastern wing regions of Himalaya-Tibetan plateau.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0540-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-015-0540-3
PMCID: PMC4489212  PMID: 26135135
DNA sequence; Evolution; Floral morphology; Gesneriaceae; Himalaya-Tibetan plateau; Petrocosmea
13.  Isocitrate dehydrogenase 1 Gene Mutation Is Associated with Prognosis in Clinical Low-Grade Gliomas 
PLoS ONE  2015;10(6):e0130872.
Isocitrate dehydrogenase 1 gene mutations are found in most World Health Organization grade II and III gliomas and secondary glioblastomas. Isocitrate dehydrogenase 1 mutations are known to have prognostic value in high-grade gliomas. However, their prognostic significance in low-grade gliomas remains controversial. We determined the predictive and prognostic value of isocitrate dehydrogenase 1 status in low-grade gliomas. The association of isocitrate dehydrogenase 1 status with clinicopathological and genetic factors was also evaluated. Clinical information and genetic data including isocitrate dehydrogenase 1 mutation, O 6-methylguanine DNA methyltransferase promoter methylation, 1p/19q chromosome loss, and TP53 mutation of 417 low-grade gliomas were collected from the Chinese Glioma Genome Atlas database. Kaplan–Meier and Cox proportional hazards regression analyses were performed to evaluate the prognostic effect of clinical characteristics and molecular biomarkers. Isocitrate dehydrogenase 1 mutation was identified as an independent prognostic factor for overall, but not progression-free, survival. Notably, isocitrate dehydrogenase 1 mutation was found to be a significant prognostic factor in patients with oligodendrogliomas, but not in patients with astrocytomas. Furthermore, O 6-methylguanine DNA methyltransferase promoter methylation (p = 0.017) and TP53 mutation (p < 0.001), but not 1p/19q loss (p = 0.834), occurred at a higher frequency in isocitrate dehydrogenase 1-mutated tumors than in isocitrate dehydrogenase 1 wild-type tumors. Younger patient age (p = 0.041) and frontal lobe location (p = 0.010) were significantly correlated with isocitrate dehydrogenase 1 mutation. Chemotherapy did not provide a survival benefit in patients with isocitrate dehydrogenase 1-mutated tumors. Isocitrate dehydrogenase 1 mutation was an independent prognostic factor in low-grade gliomas, whereas it showed no predictive value for chemotherapy response. Isocitrate dehydrogenase 1 mutation was highly associated with O 6-methylguanine DNA methyltransferase promoter methylation and TP53 mutation.
doi:10.1371/journal.pone.0130872
PMCID: PMC4482584  PMID: 26115094
14.  Irradiation Can Selectively Kill Tumor Cells while Preserving Erythrocyte Viability in a Co-Culture System 
PLoS ONE  2015;10(5):e0127181.
An understanding of how to safely apply intraoperative blood salvage (IBS) in cancer surgery has not yet been obtained. Here, we investigated the optimal dose of 137Cs gamma-ray irradiation for killing human hepatocarcinoma (HepG2), gastrocarcinoma (SGC7901), and colonic carcinoma (SW620) tumor cells while preserving co-cultured erythrocytes obtained from 14 healthy adult volunteers. HepG2, SGC7901, or SW620 cells were mixed into the aliquots of erythrocytes. After the mixed cells were treated with 137Cs gamma-ray irradiation (30, 50, and 100 Gy), tumor cells and erythrocytes were separated by density gradient centrifugation in Percoll with a density of 1.063 g/ml. The viability, clonogenicity, DNA synthesis, tumorigenicity, and apoptosis of the tumor cells were determined by MTT assay, plate colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, subcutaneous xenograft implantation into immunocompromised mice, and annexin V/7-AAD staining, respectively. The ATP concentration, 2,3-DPG level, free Hb concentration, osmotic fragility, membrane phosphatidylserine externalization, blood gas variables, reactive oxygen species levels, and superoxide dismutase levels in erythrocytes were analyzed. We found that 137Cs gamma-ray irradiation at 50 Gy effectively inhibited the viability, proliferation, and tumorigenicity of HepG2, SGC7901, and SW620 cells without markedly damaging the oxygen-carrying ability or membrane integrity or increasing the oxidative stress of erythrocytes in vitro. These results demonstrated that 50 Gy irradiation in a standard 137Cs blood irradiator might be a safe and effective method of inactivating HepG2, SGC7901, and SW620 cells mixed with erythrocytes, which might help to safely allow IBS in cancer surgery.
doi:10.1371/journal.pone.0127181
PMCID: PMC4446348  PMID: 26018651
15.  The Emerging Functions of Long Noncoding RNA in Immune Cells: Autoimmune Diseases 
Journal of Immunology Research  2015;2015:848790.
The long noncoding RNAs (lncRNAs) are RNA transcripts more than 200 nucleotides in length, which do not encode proteins. The lncRNAs are emerging as an important regulator of biological process, such as chromatin remodeling, gene transcription, protein transport, and trafficking through diverse mechanisms. The lncRNAs play crucial role in various multigenetics human diseases including cancers and neurological diseases and currently its role in autoimmune diseases is attracting many researchers. Recent studies have reported that differentiation and activation of immune cells, T cells, B cells, macrophages, and NK cells have correlation with lncRNAs, which have also an essential role in autoimmune diseases such as rheumatoid arthritis and SLE. Therefore, elucidation of the roles of lncRNAs in autoimmunity could be beneficial to understand the pathogenesis of autoimmune diseases. In this review article we attempt to highlight the recent progress regarding lncRNAs studies and summarize its role in autoimmune diseases.
doi:10.1155/2015/848790
PMCID: PMC4451983  PMID: 26090502
16.  Cisplatin combined with hyperthermia kills HepG2 cells in intraoperative blood salvage but preserves the function of erythrocytes*  
The safe use of intraoperative blood salvage (IBS) in cancer surgery remains controversial. Here, we investigated the killing effect of cisplatin combined with hyperthermia on human hepatocarcinoma (HepG2) cells and erythrocytes from IBS in vitro. HepG2 cells were mixed with concentrated erythrocytes and pretreated with cisplatin (50, 100, and 200 μg/ml) alone at 37 °C for 60 min and cisplatin (25, 50, 100, and 200 μg/ml) combined with hyperthermia at 42 °C for 60 min. After pretreatment, the cell viability, colony formation and DNA metabolism in HepG2 and the Na+-K+-ATPase activity, 2,3-diphosphoglycerate (2,3-DPG) concentration, free hemoglobin (Hb) level, osmotic fragility, membrane phosphatidylserine externalization, and blood gas variables in erythrocytes were determined. Pretreatment with cisplatin (50, 100, and 200 μg/ml) combined with hyperthermia (42 °C) for 60 min significantly decreased HepG2 cell viability, and completely inhibited colony formation and DNA metabolism when the HepG2 cell concentration was 5×104 ml−1 in the erythrocyte (P<0.01). Erythrocytic Na+-K+-ATPase activity, 2,3-DPG level, phosphatidylserine externalization, and extra-erythrocytic free Hb were significantly altered by hyperthermia plus high concentrations of cisplatin (100 and 200 μg/ml) (P<0.05), but not by hyperthermia plus 50 μg/ml cisplatin (P>0.05). In conclusion, pretreatment with cisplatin (50 μg/ml) combined with hyperthermia (42 °C) for 60 min effectively eliminated HepG2 cells from IBS but did not significantly affect erythrocytes in vitro.
doi:10.1631/jzus.B1400224
PMCID: PMC4432992  PMID: 25990057
Erythrocytes; HepG2 cells; Intraoperative blood salvage; Cisplatin; Hyperthermia
17.  The role of miR-21 in proliferation and invasion capacity of human tongue squamous cell carcinoma in vitro  
Tongue squamous cell carcinoma is one of the most common cancers, which has the highest incidence in oral maxillofacial malignant tumors. MiR-21 may promote tumorigeness by down-regulating tumor suppressing genes and/or controlling the genes for cell differentiation and apoptosis, and it has been identified as the most expressive and unusual in a number of profiling experiments. The study shows there are high expressions of miR-21 in tongue squamous cell carcinoma cell lines (Tca8113 and its high metastatic lines), especially in high metastatic lines. miR-21 silencing could suppress the capacity of proliferation, migration and invasion, arrest the cell cycle and induce apoptosis of tongue squamous cell carcinoma cell lines (Tca8113 and its high metastatic lines). All the results indicate that miR-21 will probably open a new path to the gene therapy for oral squamous cell carcinoma.
PMCID: PMC4503017  PMID: 26191145
miR-21; tongue squamous cell carcinoma; proliferation; invasion
18.  Targeting miR-21 with AS-miR-21 suppresses aggressive growth of human tongue squamous cell carcinoma in vivo  
MicroRNAs (miRNAs) are involved in many human malignant tumors. Notably, miR-21 was identified to contribute to tumorigenicity. To investigate the repressive effect of targeting miR-21 with AS-miR-21 on proliferation of tongue squamous cell carcinoma (TSCC). We established the Tca8113-luc cell line with stable luciferase expression using pGL6-luciferase (pGL6-luc) plasmid transfection. TSCC xenograft models were characterized by high tumorigenicity rate and stable growth. Intratumor injection of Oligofectamine™-mediated AS-miR-21 significantly inhibited TSCC growth. The suppression of malignant phenotype was also accompanied by decreased photon signals, rare necrosis foci, smaller nucleuses, weakly stained nucleuses, atypia reversal and tumor angiogenesis reduction. Additionally, miR-21 expression was markedly decreased in TSCC xenografts and the apoptotic index was increased. Intratumor injection of AS-miR-21 into TSCC xenografts could reduce expression of miR-21, promote apoptosis of TSCC cells and inhibit TSCC proliferation.
PMCID: PMC4503039  PMID: 26191167
Tongue squamous cell carcinoma; miR-21; AS-miR-21; gene therapy; in vivo imaging system
19.  Gene mutation profiling of primary glioblastoma through multiple tumor biopsy guided by 1H-magnetic resonance spectroscopy 
Genetic mutation has served as the biomarkers for the diagnosis and treatment of glioblastoma multiforme (GBM). However, intra-tumor heterogeneity may interfere with personalized treatment strategies based on mutation analysis. This study aimed to characterize somatic mutation profiling of GBM. We collected 33 samples from 7 patients with the primary GBM associated with different Choline (Cho) to N-acetylaspartate (NAA) index (CNI) through the frameless proton magnetic resonance spectroscopy (1H-MRS) guided biopsies and investigated multiple somatic mutations profi ling using the AmpliSeq cancer hotspot panel V2. We identifi ed 53 missense or nonsense mutations in 27 genes including some novel mutations such as APC and IDH2. The mutations in EGFR, TP53, PTEN, PIK3CA genes were presented with different frequency and the majority of the mutated gene was only shared by 1-2 samples from one patient. Moreover, we found the association of CNI with histological grade, but there was no signifi cant change of CNI in the presence of TP53, EGFR and PTEN mutations. These data suggest that gene mutations constitute a heterogeneous marker for primary GBM which may be independent of intra-tumor morphological phenotypes of GBM; therefore, gene mutation markers could not be determined from a small number of needle biopsies or only confi ned to the high-grade region.
PMCID: PMC4503105  PMID: 26191234
Mutation profi ling; heterogeneity; glioblastoma multiforme; proton magnetic resonance spectroscopy; biopsy
20.  In our own image? Emotional and neural processing differences when observing human–human vs human–robot interactions 
Notwithstanding the significant role that human–robot interactions (HRI) will play in the near future, limited research has explored the neural correlates of feeling eerie in response to social robots. To address this empirical lacuna, the current investigation examined brain activity using functional magnetic resonance imaging while a group of participants (n = 26) viewed a series of human–human interactions (HHI) and HRI. Although brain sites constituting the mentalizing network were found to respond to both types of interactions, systematic neural variation across sites signaled diverging social-cognitive strategies during HHI and HRI processing. Specifically, HHI elicited increased activity in the left temporal–parietal junction indicative of situation-specific mental state attributions, whereas HRI recruited the precuneus and the ventromedial prefrontal cortex (VMPFC) suggestive of script-based social reasoning. Activity in the VMPFC also tracked feelings of eeriness towards HRI in a parametric manner, revealing a potential neural correlate for a phenomenon known as the uncanny valley. By demonstrating how understanding social interactions depends on the kind of agents involved, this study highlights pivotal sub-routes of impression formation and identifies prominent challenges in the use of humanoid robots.
doi:10.1093/scan/nsv043
PMCID: PMC4631149  PMID: 25911418
impression formation; mind attributions; person construal; person dyads; social robotics
21.  Laforin-malin complex degrades polyglucosan bodies in concert with glycogen debranching enzyme and brain isoform glycogen phosphorylase 
Molecular neurobiology  2013;49(2):645-657.
In Lafora disease (LD), deficiency of either EPM2A or NHLRC1, the genes encoding the phosphatase laforin and E3 ligase respectively, causes massive accumulation of less-branched glycogen inclusions, known as Lafora bodies, also called polyglucosan bodies (PBs), in several types of cells including neurons. The biochemical mechanism underlying the PB accumulation, however, remains undefined. We recently demonstrated that laforin is a phosphatase of muscle glycogen synthase (GS1) in PBs, and that laforin recruits malin, together reducing PBs. We show here that accomplishment of PB degradation requires a protein assembly consisting of at least four key enzymes: laforin and malin in a complex, and the glycogenolytic enzymes, glycogen debranching enzyme 1 (AGL1) and brain isoform glycogen phosphorylase (GPBB). Once GS1-synthesized polyglucosan accumulates into PBs, laforin recruits malin to the PBs where laforin dephosphorylates, and malin degrades the GS1 in concert with GPBB and AGL1, resulting in a breakdown of polyglucosan. Without fountional laforin-malin complex assembled on PBs, GPBB and AGL1 together are unable to efficiently breakdown polyglucosan. All these events take place on PBs and in cytoplasm. Deficiency of each of the four enzymes causes PB accumulation in the cytoplasm of affected cells. Demonstration of the molecular mechanisms underlying PB degradation lays a substantial biochemical foundation that may lead to understanding how PB metabolizes and why mutations of either EPM2A or NHLRC1 in humans cause LD. Mutations in AGL1 or GPBB may cause diseases related to PB accumulation.
doi:10.1007/s12035-013-8546-z
PMCID: PMC3954894  PMID: 24068615
Laforin; Malin; AGL1; GPBB; Polyglucosan body; Polyglucosan; Lafora disease
22.  Matrix metalloproteinase 9 level as an indicator for restenosis following cervical and intracranial angioplasty and stenting 
Neural Regeneration Research  2015;10(4):631-635.
Cervical and intracranial angioplasty and stenting is an effective and safe method of reducing the risk of ischemic stroke, but it may be affected by in-stent restenosis. The present study investigated serum level of matrix metalloproteinase 9 as a predictor of restenosis after 40 patients underwent cervical and/or intracranial angioplasty and stenting. Results showed that restenosis occurred in 30% (3/10) of patients when the serum level of matrix metalloproteinase 9 at 3 days after surgery was 2.5 times higher than preoperative level. No restenosis occurred when the serum level of matrix metalloproteinase 9 at 3 days after surgery was not 2.5 times higher than preoperative level. Restenosis occurred in 12% (2/17) of patients when the serum level of matrix metalloproteinase 9 was higher than preoperative level for more than 30 days after surgery, but only occurred in 4% (1/23) of patients when the serum level of matrix metalloproteinase 9 was higher than preoperative level for less than 30 days after surgery. However, the differences observed were not statistically significant (P > 0.05). Experimental findings indicate that when the serum level of matrix metalloproteinase 9 is 2.5 times higher than preoperative level at 3 days after cervical and intracranial angioplasty and stenting, it may serve as a predictor of in-stent restenosis.
doi:10.4103/1673-5374.155439
PMCID: PMC4424758  PMID: 26170826
nerve regeneration; matrix metalloproteinase 9; cervical and intracranial angioplasty and stenting; restenosis; intracranial artery stenosis; neural regeneration
23.  Shot-noise Limited Faraday Rotation Spectroscopy for Detection of Nitric Oxide Isotopes in Breath, Urine, and Blood 
Scientific Reports  2015;5:9096.
Measurement of NO and/or its metabolites in the various body compartments has transformed our understanding of biology. The inability of the current NO measurement methods to account for naturally occurring and experimental NO isotopes, however, has prevented the scientific community from fully understating NO metabolism in vivo. Here we present a mid-IR Faraday rotation spectrometer (FRS) for detection of NO isotopes. The instrument utilizes a novel dual modulation/demodulation (DM) FRS method which exhibits noise performance at only 2 times the fundamental quantum shot-noise level and provides the record sensitivity in its class. This is achieved with a system that is fully autonomous, robust, transportable, and does not require cryogenic cooling. The DM-FRS enables continuous monitoring of nitric oxide isotopes with the detection limits of 3.72 ppbv/Hz1/2 to14NO and 0.53 ppbv/Hz1/2 to15NO using only 45 cm active optical path. This DM-FRS measurement method can be used to improve the performance of conventional FRS sensors targeting other radical species. The feasibility of the instrument to perform measurements relevant to studies of NO metabolism in humans is demonstrated.
doi:10.1038/srep09096
PMCID: PMC4357895  PMID: 25767064
24.  Recurrent gain-of-function USP8 mutations in Cushing's disease 
Cell Research  2015;25(3):306-317.
Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.
doi:10.1038/cr.2015.20
PMCID: PMC4349249  PMID: 25675982
Cushing's disease; pituitary adenomas; USP8; mutation; whole-exome sequencing
25.  Successful Diagnosis of Hypothalamitis Using Stereotactic Biopsy and Treatment 
Medicine  2015;94(5):e447.
Abstract
Existing methods could not discriminate between inflammation and other diseases, which might occur in hypothalamus, such as neurogliocytoma, germinoma, lymphoma, and so on. Given its location in the brain, it was not practical to obtain tissue using standard surgical methods.
We reported the first case of a patient with hypothalamus lesion, who was diagnosed as hypothalamitis by stereotactic biopsy. This precise diagnosis allowed proper medical treatments.
We reported a case of a patient with hypothalamus lesion. To confirm the diagnosis, with informed consent from the family, a successful stereotactic hypothalamic biopsy was performed by neurosurgeons.
Immunohistochemical results of biopsy specimens from the hypothalamus lesion revealed inflammatory infiltrates, which were composed mainly of lymphocytes, plasma cells, and histiocytes, and were stained with leucocyte common antigen (LCA), κ 1, and cluster of differentiation 18. Final pathological diagnosis was lymphoplasmacytic proliferative, granuloma-like inflammatory pseudotumor, with immunoglobulin G deposition. Based on the pathological diagnosis, we treated the patient with glucocorticoid and azathioprine. Remarkable improvements were observed in both magnetic resonance imaging (MRI) and patient's symptoms.
Stereotactic biopsy for intracranial lesions was a reliable and relatively safe procedure, even for hypothalamus. It was an effective method with high diagnostic yield. With correct diagnosis, it was much easier to choose correct treatment.
doi:10.1097/MD.0000000000000447
PMCID: PMC4602714  PMID: 25654381

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